Desensitization to a persistent extracellular signal is a critical characteristic of G protein signaling and multiple mechanism exist to achieve this aim. Regulators of G protein signaling (RGS) proteins are a newly identified class of proteins that play an important role in the desensitization process by acting on G protein subunits. RGS9 is unique among RGS proteins in that it is nearly exclusively expressed in regions of the brain that receive dopaminiergic innervation. Furthermore, RGS9 is uniquely down regulated in response to dopamine release after treatment with amphetamine. Although the exact in vivo function of RGS9 remains unclear, the involvement of dopaminergic neurotransmission in many neuropsychiatric disorders including Parkinson s disease, schizophrenia and drug abuse points to RGS9 as a potential therapeutic target for these disorders. This proposal will provide an integrated analysis of RGS9 expression, regulation and function. We will identify the neuronal cell subtypes that express RGS9 in human and rat basal ganglia. Furthermore, we will examine alterations in RGS9 expression by acute and cronic manipulation of dopaminergic and glutamatergic neurotransmission. RGS9 has recently been cloned and is a complex protein with 3 identifiable domains in addition to its RGS domain. The functions of these various domains are not yet clear but they are likely to be involve din determining the specificity of interactions with other signaling molecules. Molecular reagents, including antibodies, epitope tagged RGS9 expression constructs and domain mutations have been generated that will allow a structure-function analysis of RGS9. These analyses will include the subcellular localization of the RGS9 proteins, its interaction with different G protein subunits and identification of novel binding partners for RGS9. A better understanding of RGS regulation and function will help to clarify how dopamine and dopaminergic agents produce their effects. Our specific aims our: Specific Aim 1. Determine the cellular localization and dopaminergic regulation of RGS9 in the striatum. Specific Aim 2. Identify and analyze RGS signaling partners. Specific Aim 3. Analyze RGS9 targeting and function.